What is the recommended regimen of recombinant human chorionic gonadotropin (hCG) and recombinant follicle‑stimulating hormone (FSH) for an adult male with secondary hypogonadism, low testosterone, symptoms, and a desire to preserve or restore fertility?

Recombinant hCG Plus FSH for Secondary Hypogonadism with Fertility Preservation

For adult men with secondary hypogonadism, low testosterone, symptoms, and a desire to preserve or restore fertility, the recommended regimen is recombinant human chorionic gonadotropin (hCG) 1,500–2,500 IU administered 2–3 times weekly (approximately 3,500–5,000 IU total per week), followed by the addition of recombinant FSH 75–150 IU subcutaneously 2–3 times weekly after 3–6 months if sperm counts remain inadequate. 1, 2

Why Gonadotropin Therapy Is Mandatory

• Testosterone replacement therapy is absolutely contraindicated in any man seeking fertility preservation because exogenous testosterone suppresses the hypothalamic-pituitary axis, causing oligospermia or azoospermia that may persist for months to years after discontinuation 1, 2, 3
• hCG directly stimulates testicular Leydig cells to produce intratesticular testosterone concentrations 50–100 times higher than serum levels, which is essential for spermatogenesis, while simultaneously normalizing serum testosterone to treat hypogonadal symptoms 2
• Combined hCG and FSH therapy provides optimal outcomes for fertility preservation in secondary hypogonadism, with spermatogenesis achieved in approximately 80% of men and pregnancy rates around 50% after 12–24 months of treatment 1, 4

Treatment Protocol

Phase 1: hCG Monotherapy (Months 0–6)

• Initiate hCG at 1,500–2,500 IU subcutaneously or intramuscularly 2–3 times weekly (total weekly dose approximately 3,500–5,000 IU) 1, 2, 5
• Monitor serum testosterone at 3 months; testosterone typically normalizes within 3–6 months of hCG initiation 2, 6
• Perform first semen analysis at 6 months to assess early spermatogenic response 2, 6

Phase 2: Add FSH if Needed (After Month 6)

• If sperm counts remain inadequate after 6 months of hCG monotherapy, add recombinant FSH 75–150 IU subcutaneously 2–3 times weekly 1, 2, 6
• The combination of hCG plus FSH is superior to hCG alone for inducing spermatogenesis, particularly in men with more severe gonadotropin deficiency 1, 4, 6
• Continue combination therapy for 12–24 months total, as sperm may not appear until 6–12 months and optimal counts often require 18–24 months 2, 4, 6

Monitoring Schedule

• Baseline: Measure morning total testosterone (8–10 AM on two occasions), LH, FSH, prolactin, and perform semen analysis to document azoospermia 1, 2
• Month 3: Repeat testosterone, LH, FSH to confirm testosterone normalization 2
• Month 6: First semen analysis; if azoospermic, add FSH 2, 6
• Every 3–6 months thereafter: Repeat semen analysis until pregnancy is achieved or adequate sperm are banked 2, 6
• Monitor for gynecomastia, the most common side effect, caused by hCG-stimulated aromatase activity and increased estradiol 4

Predictors of Treatment Success

• Larger baseline testicular volume (>4 mL) predicts higher likelihood of successful spermatogenesis, as it indicates greater residual testicular function 4, 6
• Post-pubertal onset of hypogonadism (versus congenital) is associated with better response rates 4
• Lower body mass index correlates with improved spermatogenic response 6
• Higher baseline inhibin B concentrations predict better outcomes 4
• Absence of cryptorchidism history improves prognosis 4

Expected Outcomes

• Spermatogenesis is restored in approximately 80–84% of men with secondary hypogonadism treated with hCG plus FSH 4, 6
• Sperm concentrations ≥1.5 × 10⁶/mL are achieved in approximately 69% of men after 12–18 months of combination therapy 6
• Spontaneous pregnancy rates approach 50% with adequate treatment duration 4
• Testicular volume increases in nearly all patients during treatment, reflecting restored spermatogenesis 4, 7

Alternative: Clomiphene Citrate

• For men with partial (not complete) hypogonadotropic hypogonadism who retain some endogenous gonadotropin activity, clomiphene citrate 25–50 mg three times weekly may be considered as a less expensive oral alternative that stimulates endogenous LH and FSH secretion 2, 3
• Clomiphene is ineffective in complete hypogonadotropic hypogonadism (LH and FSH <1.5 IU/L) because there is insufficient pituitary reserve to respond to estrogen-receptor blockade 2
• Clomiphene may be added to hCG in cost-sensitive settings to reduce the need for injectable FSH, though this approach has less robust evidence than hCG plus FSH 2

Critical Pitfalls to Avoid

• Never initiate testosterone replacement in a man who desires current or future fertility; this causes azoospermia that may take 6–24 months to reverse after discontinuation, and some men never recover 1, 2, 3
• Do not use gonadotropin therapy in primary hypogonadism (elevated LH/FSH with low testosterone), as the testes cannot respond to gonadotropin stimulation; these men require testosterone replacement and should be counseled that fertility preservation is not possible with medical therapy 1, 3
• Do not expect immediate results; sperm may not appear until 6–12 months of combination therapy, and optimal counts often require 18–24 months 2, 4, 6
• Do not discontinue therapy prematurely; men who undergo repeated cycles of gonadotropin therapy have higher cumulative success rates 4

When Gonadotropin Therapy Fails

• If no sperm are detected after 12–18 months of hCG plus FSH, consider microsurgical testicular sperm extraction (micro-TESE) followed by intracytoplasmic sperm injection (ICSI) 2
• Approximately 10% of men with secondary hypogonadism experience spontaneous reversal of hypogonadism during or after gonadotropin therapy, though the mechanism is not fully understood 4